Submissions for variant NM_006363.6(SEC23B):c.53G>A (p.Arg18His)

gnomAD frequency: 0.00004  dbSNP: rs905074313

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV002276098	SCV002563678	likely pathogenic	not provided	2024-12-01	criteria provided, single submitter	clinical testing	SEC23B: PM2, PM5, PP3, PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101567	SCV003247253	likely pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 18 of the SEC23B protein (p.Arg18His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with dyserythropoietic anemia type 2 (PMID: 19561605, 27471141). ClinVar contains an entry for this variant (Variation ID: 1701418). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SEC23B protein function with a positive predictive value of 95%. This variant disrupts the p.Arg18 amino acid residue in SEC23B. Other variant(s) that disrupt this residue have been observed in individuals with SEC23B-related conditions (PMID: 27471141), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526922	SCV005039215	uncertain significance	not specified	2024-03-22	criteria provided, single submitter	clinical testing	Variant summary: SEC23B c.53G>A (p.Arg18His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251472 control chromosomes. c.53G>A has been reported in the literature in at-least two individuals affected with Congenital dyserythropoietic anemia, type II (Iolascon_2010, Schwarz_ 2009). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20015893, 19561605). ClinVar contains an entry for this variant (Variation ID: 1701418). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785559	SCV005398269	pathogenic	Congenital dyserythropoietic anemia, type II	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Congenital dyserythropoietic anaemia type II (CDA; MIM#224100). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 7 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (highest allele count v3: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. p.(Arg18Cys) has been reported in an individual with CDA and compound heterozygous with p.(Arg14Trp) (PMID: 27471141). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least four compound heterozygous individuals with CDA (PMID: 20015893, 25044164, 27471141). In addition, it has been classified as a variant of uncertain significance and likely pathogenic by diagnostic laboratories in ClinVar. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1101 - Very strong and specific phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_006363.6(SEC23B):c.279+2T>C) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV003101567	SCV005656373	likely pathogenic	Congenital dyserythropoietic anemia, type II; Cowden syndrome 7	2024-04-04	criteria provided, single submitter	clinical testing
GeneDx	RCV002276098	SCV005874623	likely pathogenic	not provided	2024-08-26	criteria provided, single submitter	clinical testing	Observed in patients with features of congenital dyserythropoietic anemia type II who also possessed a second SEC23B variant (PMID: 19561605, 27471141, 20015893); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19561605, 20015893, 27471141, 31104444, Melanie2012[poster])